OBJECTIVE: To determine whether topical application of naltrexone prevents exuberant granulation tissue formation with neovascularization in diabetic rat corneas. METHODS: Diabetes was induced with streptozotocin. A 5-mm corneal abrasion at 9 or 11 weeks was treated topically for 7 days (4 times daily) with naltrexone or a sterile vehicle. RESULTS: Within 2 to 5 days after reepithelialization, diabetic rats given the sterile vehicle had a 41% incidence of corneal lesions represented by exuberant granulation tissue with corneal neovascularization extending from the limbus. These lesions exhibited edema, cellular and vascular inflammation, and disruption of stromal lamella by fibrovascular tissue and calcium mineralization, but infection was not detected. No corneal lesions were recorded in the diabetic group treated with naltrexone or the control group given the sterile vehicle. Diabetic rats with corneal lesions given the sterile vehicle reepithelialized more slowly than diabetic rats given the sterile vehicle without such lesions, but no difference in blood glucose levels were noted. CONCLUSIONS: Using a minimally invasive model in diabetic rats, topical naltrexone normalizes corneal wound healing and prevents neovascularization. CLINICAL RELEVANCE: Direct application of naltrexone may serve as an important strategy for facilitating corneal healing and inhibiting corneal neovascularization.